The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, and opioids on physiology of this system. The NAc medium spiny GABAergic neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by drugs of abuse, suggesting that this action may contribute to the rewarding properties of these drugs. To investigate the actions of cannabinoids (CBs) in the NAc, we are utilizing whole-cell recordings from MSNs in rat brain slices. Accomplishments attributable to this project in the past year include the establishment of a chronic delta-9-tetrahydrocannabinol (THC) treatment paradigm that successfully resulted in tolerance to various pharmacological effects of THC, particularly cross-tolerance between delta-9-tetrahydrocannabinol, the active ingredient in marijuana, and opiates. This tolerance was noted as a diminished diminished capacity for inhibition of field excitatory postsynaptic potentials (EPSPs)in the nucleus accumbens shell by both cannabinoid and opioid agonists. These data appear to provide a mechanistic explanation for the often-observed interactions between opioid and cannabinoid systems in behavioral studies. Ongoing studies with Dr. Bruce Hope are also investigating the effects of repeated cocaine treatment on synaptic inputs to MSNs. To do this, we are using rats that express a fluorescent marker in a discrete population of MSNs as a result of cocaine sensitization. By visualizing these specific neurons in our slice preparation, we can perform electrophysiological recordings from these cells and assess the mechanisms supporting cocaine sensitization. These studies are ongoing, and additional data are to be presented at the 2005 Society for Neuroscience Annual Meeting.